Infection with Bacillus anthracis leads to bleeding, tissue swelling, and thrombosis, contributing significantly to illness and death from anthrax. Therefore, our long-term objective is to develop therapies targeting vascular damage underlying these events. To establish the scientific basis for these therapies, this proposal will use a murine model to characterize anthrax-induced vascular damage at a structural and molecular level. In the first aim, we will define the ultrastructural basis for acute vascular damage through histological time course studies. As part of this aim, the contributions of anthrax lethal toxin and edema toxin towards vascular pathology will also be determined. The second aim will explore the physiological basis for vessel damage through analysis and modulation of pathways known to contribute to vascular pathology in other systems. In keeping with the exploratory nature of the R21 funding mechanism, this aim will survey a number of possible scenarios, thereby giving us a more complete understanding through both positive and negative findings. As part of this exploration, we hope to identify and test new therapeutic strategies. [unreadable] [unreadable]